This proposal is the competitive renewal of a K24, Midcareer Investigator Award in FOR (K24 CA97588). The Grant had been titled Clinical Investigation in Tumor Immunotherapy. A different approach to cancer therapy forms the basis of this proposal. Instead of tumor immunotherapy, the therapy applied is biologically targeted, signal transduction inhibitors administered to melanoma patients. These changes have been taken due to the strengths of this institution (Vanderbilt) and my belief that this approach to cancer therapy has potential for success in patients not presently observed with tumor immunotherapy. In this proposal, the orientation remains clinical translational research and the development of a program to best mentor junior clinical investigators. Melanoma is one of the fastest growing tumor types in the US. For metastatic disease, immunotherapy has been the primary approach to treatment, but has so far not fulfilled its great promise. Therapy targeting (inhibiting) a constitutively activated, signaling pathway critical to the cancer's growth can provide a remarkable clinical benefit, (i.e. imatinib in CML and GIST, traztuzumab in breast cancer, erlotinib and gefitinib in NSCLC). The success in these malignancies with new therapeutics provides an impetus to search for similarly effective agents in other cancers. In 2002, B-RAF gain of function mutations predominantly at V600E were identified in 66% of melanomas tested. Its inhibition with either a kinase inhibitor or RNAi led to tumor regression in animal xenografts . Other mutations cooperate with B-RAF including MITF overexpression, CDK4 or CCND1 amplification, PTEN loss, and activation of the Akt pathway. The identification of prevalent mutations suggest that therapy targeting gain of function mutations, overexpressed genes, or activated pathways could provide a major clinical benefit without unacceptable toxicity. The availability of new agents that can target activated pathways important to melanoma is exciting. These drugs will require careful evaluation by well-trained clinical investigators with special attention to what is important to a clinical response. This K24 grant and the melanoma program is vested in training these . translational investigators. Through access to seminars, conferences, tumor boards, a tumor repository, and opportunities in clinical and laboratory training, junior clinical investigators will get excellent training opportunities. The K24 activities will be integrated with the T32, K12 training grants, and the MSCI courses.